The function of the nervous system depends upon specific neural connections. Our research is focused on factors from peripheral target tissues like skin that govern the development and maintenance of the sensory nervous system. While target tissues have well-known effects on neuronal survival, this proposal focuses on additional differentiative actions by skin factors. This proposal is based on our discovery that activin, a member of the Transforming Growth Factor beta superfamily, is a potent differentiative factor for sensory neurons that increases neuropeptides responsible for pain perception and inflammation. We propose that during development and following adult skin wounds, activin derived from skin acts on cutaneous neurons to increase sensory neuropeptides essential for pain sensation and vasodilatory events essential for wound healing. To test this hypothesis, we will define how the activin signal initiated at nerve terminals in skin is conveyed to the sensory neuronal cell body to identify potential molecular targets for therapeutic intervention in pain management. Not all sensory neurons respond to activin, and activation-specific antibodies will be used to identify the pool of responsive neurons. Reduction of intracellular smad signaling will be used to test if these signals are essential for activin's biological effects. Additional characteristics of embryonic and adult neurons altered by activin will be identified. The biochemical and physiological consequences of activin induction of neuropeptides will be tested by modulating activin to alter neuropeptides and pain sensation following injury. The overall aim of this grant its to understand the mechanism by which activin and activin regulated signaling pathways exert their effects on the development and plasticity of the nervous system. This project will provide important information on the role of target-derived activin in the coordinated physiological response to neural injury. These studies will provide a molecular basis for intervention in inflammatory pain syndromes and may offer new diagnostic and therapeutic tools in clinical medicine. [unreadable] [unreadable]